Compounds and compositions for delivering active agents

ABSTRACT

Modified, amino acid compounds useful in the delivery of active agents are provided. The active agents can be peptides, such as rhGH. Methods of administration, such as oral, subcutaneous, sublingual, and intranasal administration, are provided, and methods of preparation of the modified amino acid compound are provided.

[0001] This application is a Continuation-In-Part of application Ser.No. 08/414,654, filed Mar. 31, 1995 and Application Serial No.60/003,111, filed Sep. 1, 1995.

FIELD OF THE INVENTION

[0002] The present invention relates to compounds for delivering activeagents, and particularly biologically or chemically active agents suchas, for example, bioactive peptides and the like. These compounds areused as carriers to facilitate the delivery of a cargo to a target. Thecarriers are modified amino acids and are well suited to formnon-covalent mixtures with biologically-active agents for oraladministration to animals. Methods for the preparation and for theadministration of such compositions are also disclosed.

BACKGROUND OF THE INVENTION

[0003] Conventional means for delivering active agents are oftenseverely limited by biological, chemical, and physical barriers.Typically, these barriers are imposed by the environment through whichdelivery, occurs, the environment of the target for delivery, or thetarget itself.

[0004] Biologically or chemically active agents are particularlyvulnerable to such barriers. For example in the delivery to animals ofpharmacological and therapeutic agents, barriers are imposed by thebody. Examples of physical barriers are the skin and various organmembranes that must be traversed before reaching a target. Chemicalbarriers include, but are not limited to, pH variations, lipidbi-layers, and degrading enzymes.

[0005] These barriers are of particular significance in the design oforal delivery systems. Oral delivery of many biologically or chemicallyactive agents Would be the route of choice for administration to animalsif not for biological, chemical, and physical barriers such as varyingpH in the gastro-intestinal (GI) tract, powerful digestive enzymes, andactive agent impermeable gastro-intestinal membranes. Among the numerousagents which are not typically amenable to oral administration arebiologically or chemically active peptides, such as calcitonin andinsulin; polysaccharides, and in particular mucopolysaccharidesincluding, but not limited to, heparin; heparinoids; antibiotics; andother organic substances. These agents are rapidly rendered ineffectiveor are destroyed in, the gastro-intestinal tract by acid hydrolysis,enzymes, or the like.

[0006] Earlier methods for orally administering vulnerablepharmacological agents have relied on the co-administration of adjuvants(e.g., resorcinols and non-ionic surfactants such as polyoxyethyleneoleyl ether and n-hexadecylpolyethylene ether) to increase artificiallythe permeability of the intestinal walls, as well as theco-administration of enzymatic inhibitors (e.g., pancreatic trypsininhibitors, diisopropylfluorophosphate (OFF) and trasylol) to inhibitenzymatic degradation.

[0007] Liposomes have also been described as drug delivery systems forinsulin and heparin. See, for example, U.S. Pat. No. 4,239,754; Patel etal. (1976), FEBS Letters, Vol. 62, pg. 60; and Hashimoto et al. (1979),Endocrinology Japan, Vol. 26, pg. 337.

[0008] However, broad spectrum use of such drug delivery systems isprecluded because: (1) the systems require toxic amounts of adjuvants orinhibitors; (2) suitable low molecular weight cargos, i.e. active agentsare not available; (3) the systems exhibit poor stability and inadequateshelf life; (4) systems are difficult to manufacture; (5) the systemsfail to protect the active agent (cargo); (6) the systems adverselyalter the active agent; or (7) the systems fail to allow or promoteabsorption of the active agent.

[0009] More recently, microspheres of artificial polymers of mixed aminoacids (proteinoids) have been used to deliver pharmaceuticals. Forexample, U.S. Pat. No. 4,925,673 describes drug-containing proteinoidmicrosphere carriers as well as methods for their preparation and use.These proteinoid microspheres are useful for thc delivery of a number ofactive active agents.

[0010] There is still a need in the art, for simple, inexpensivedelivery systems which are easily prepared and which can deliver a broadrange of active agents.

SUMMARY OF THE INVENTION

[0011] Compositions which are, useful in the delivery of active agentsare provided. These compositions are include at least one active agent,and preferably a biologically or chemically active agent, and at leastone of the following compounds I-CXXIII, or salts thereof.

I

II

III

IV

V

VI

VII

VIII

IX

X

IX

X

XI

XII

XIII

XIV

XVII

XVIII

XIX

XX

XXI

XXII

XXIII

XXIV

XXV

XXVI

XXVII

XXVIII

XXIX

XXX

XXXI

XXXII

XXIII

XXXIV

XXXV

XXXVI

A Compound n m X XXXVII 0 0 4-Cl XXXVIII 3 0 H XXXIX 3 1 4-CH₃ XL 3 12-F XLI 3 1 2-CH₃ XLII 3 0 3-CF₃ XLIII 3 4 H XLIV 3 0 3-Cl XLV 3 0 3-FXLVI 3 0 3-CH₃ XLVII 0 0 2-CF₃ XLVIII 1 2 H XLIX 3 2 2-F L 3 03,4-OCH₂O— LI 3 0 2-COOH LII 1 0 2-OH LIII 3 0 2,6-dihydroxy LIV 2 02-OH LV 0 0 2,4-difluoro LVI 2 0 2,6-dihydroxy LVII 0 0 4-CF₃ LVIII 3 03-NMe₂ LIX 2 0 3-NMe₂ XLIX 3 2 2-F L 3 0 3,4-OCH₂O— LI 3 0 2-COOH LII 10 2-OH LIII 3 0 2,6-dihydroxy LIV 2 0 2-OH LV 0 0 2,4-difluoro LVI 2 02,6-dihydroxy LVII 0 0 4-CF₃ LVIII 3 0 3-NMe₂ LIX 2 0 3-NMe₂ LX 3 02,6-dimethyl LXI 3 0 2-NO₂ LXII 3 0 2-CF₃ LXIII 3 0 4-n-Pr LXIV 3 02-NH₂ LXV 3 0 2-OCH₃ LXVI 3 0 3-NO₂ LXVII 3 0 3-NH₂ LXVIII 2 0 2-NO₂LXIX 2 0 2-NH₂ LXX 3 0 2-OCF₃ LXXI 2 0 2-OCH₃ LXXII 2 0 2-OCF₃

B Compound n X LXXIII 3 4-CF₃ LXXIV 1 2-F LXXV 1 4-CF₃ LXXVI 33,4-dimethoxy LXXVII 0 3-OCH₃ LXXVIII 3 3-OCH₃ LXXIX 3 2,6-difluoro LXXX3 4-CH₃ LXXXI 1 4-OCH₃ LXXXII 2 2-F LXXXIII 0 2-F LXXXIV 2 4-OCH₃ LXXXV0 2-OCH₃ LXXXVI 2 2-OCH₃ LXXXVII 0 4-CF₃ LXXXVIII 3 3-F LXXXIX 3 2-OCH₃

C Compound n m X XC 3 0 2-carboxycyclohexyl XCI 3 3 cyclohexyl XCII 3 02-adamantyl XCIII 3 0 1-morpholino

D Compound m XCIV 0 XCV 3

E Compound X XCVI OH XCVII ═O

F Compound n XCVIII 0 XCIX 2

C

CI

CII

CIII

CIV

CV

CVI

CVII

CVIII

CIX

CX

G Compound n m X CXI 6 0 2-OH CXII 7 3 H CXIII 7 0 2-I CXIV 7 0 2-Br CXV7 0 3-NO₂ CXVI 7 0 3-N(CH₃)₂ CXVII 7 0 2-NO₂ CXVIII 7 0 4-NO₂ CXIX 9 02-OH

H Compound X CXX 1-morpholino CXXI O-t-Butyl CXXII CH(CH₂Ph)NC(O)O-t-BuCXXIII 2-hydroxyphenyl

[0012] It has been discovered that organic acid compounds, and theirsalts, having an aromatic amide group, having a hydroxy groupsubstituted in the ortho position on the aromatic ring, and a lipophilicchain with from about 4 carbon atoms to about 20 atoms in the chain areuseful as carriers for the delivery of active agents. In a preferredform the lipophilic chain can have from 5 to 20 carbon atoms.

[0013] Compositions comprising the carrier compounds discussed above andactive agents have been shown effective in delivering active agents toselected biological systems. These compositions include at least oneactive agent which is preferably a biologically or chemically activeagent, and at least one carrier compound having the formula

2-HO—Ar—CONR⁸—R⁷—COOH

[0014] wherein Ar is a substituted or unsubstituted phenyl or naphthyl;

[0015] R⁷ is selected from the group consisting of C₄ to C₂₀ alkyl, C₄to C₂₀ alkenyl, phenyl, naphthyl, (C₁ to C₁₀ alkyl) phenyl, (C₁ to C₁₀alkenyl) phenyl, (C₁ to C₁₀ alkyl) naphthyl, (C₁ to C₁₀ alkenyl)naphthyl, phenyl (C₁ to C₁₀ alkyl), phenyl (C₁ to C₁₀ alkenyl), naphthyl(C₁ to C₁₀ alkyl), and naphthyl (C₁ to C₁₀ alkenyl);

[0016] R⁸ is selected from the group consisting of hydrogen, C₁ to C₄alkyl C₁ to C₄ alkenyl, hydroxy, and C₁ to C₄ alkoxy;

[0017] R⁷ is optionally substituted with C₁ to C₄ alkyl, C₁ to C₄alkenyl, C₁ to C₄ alkoxy, —OH, —SH and —CO₂R⁹ or any combinationthereof;

[0018] R⁹ is hydrogen, C₁ to C₄ alkyl or C₁ to C₄ alkenyl;

[0019] R⁷ is optionally interrupted by oxygen, nitrogen, sulfur or anycombination thereof;

[0020] With the proviso that the compounds are not substituted with anamino group in the position alpha to the acid group or salts thereof.

[0021] The preferred R⁶ groups are of C₄ to C₂₀ alkyl and C₄ to C₂₀alkenyl. The most preferred R⁶ groups are C₅ to C₂₀ alkyl and C₅ to C₂₀alkenyl.

[0022] A preferred carrier compound can have the formula

[0023] wherein R⁷ is defined above.

[0024] Further contemplated by the present invention are dosage unitforms that include these compositions.

[0025] Also contemplated is a method for preparing these compositionswhich comprises mixing at least one active agent with at least onecompound as described above, and optionally, a dosing vehicle.

[0026] In an alternative embodiment, these non-toxic compounds areorally administered to animals as part of a delivery system by blendingor mixing the compounds with an active agent prior to administration.

[0027] Further provided is a method for the preparation of a compoundhaving the formula

[0028] Wherein Y is

[0029] or SO₂;

[0030] R¹ is C₃-C₂₄ alkyd C₂-C₂₀ alkenyl, C₂-C₂₀ alkyne, cycloalkyl, oraromatic;

[0031] R² is hydrogen, C₁-C₄ alkyl, or C₂-C₄ alkenyl; and

[0032] R³ is C₁-C₇ alkyl, C₃-C₁₀ cycloalkyl aryl, thienyl, pyrrolo, or

[0033] pyridyl, where R³ is optionally substituted by one or more C₁-C₅alkyl group, C₂-C₄ alkenyl group, F, Cl, OH, SO₂, COOH, or

[0034] said method comprising,

[0035] (a) releasing in water and the presence of a base, a compoundhaving the formula

[0036] with a compound having the formula

R³—Y—X, wherein

[0037] Y, R¹, R², and R³ are as above and X is a leaving group.

DESCRIPTION OF THE DRAWINGS

[0038]FIG. 1 is a graphic illustration of the results of subcutaneousinjection of rhGH composition in rats.

[0039]FIG. 2 is a graphic illustration of the results of Sublingual(SL), intranasal (IN), and intracolonic (IC) dosing of rhGH in-rats.

[0040]FIG. 3 is a graphic illustration of the results of, intracolonicdosing of delivery of heparin with compound XXXI carrier.

DETAILED DESCRIPTION OF THE INVENTION

[0041] The specific compositions of the present invention include anactive agent and a modified amino acid. These compositions may be usedto deliver various active agents through various biological chemical,and physical barriers and are particularly suited for delivering activeagents which are subject to environmental degradation. The compositionsof the subject invention are particularly useful for delivering oradministering biologically or chemically active agents to any animalssuch as birds; mammals, such as primates and particularly humans, andinsects.

[0042] Other advantages of the present invention include the use of easyto prepare, inexpensive raw materials. The compositions and theformulation methods of the present invention are cost effective, simpleto perform, and amenable to industrial scale up for commercialproduction.

[0043] Subcutaneous, sublingual, and intranasal coadministration of anactive agent, such as recombinant human growth hormone (rhGH), and thedelivery agents, and particularly proteins, described herein results inan increased bioavailability of the active agent compared toadministration of the active agent alone. A similar result is obtainedby coadministration of salmon calcitonin with the delivery agents, inrats. Data supporting these findings are presented in the examples.

[0044] Active Agents

[0045] Active agents suitable for use in the present invention includebiologically or chemically active agents, chemically active agents,including, but not limited to, fragrances, as well as other activeagents such as, for example, cosmetics.

[0046] Biologically or chemically active agents include, but arenot-limited to pesticides, pharmacological agents, and therapeuticagents. For example, biologically or chemically active agents suitablefor use in the present invention include, but are not limited to,peptides, and particularly small peptides; hormones, and particularlyhormones which by themselves do not or only a fraction of theadministered dose passes through the gastro-intestinal mucosa and/or aresusceptible to chemical cleavage by acids and enzymes in thegastro-intestinal tract; polysaccharides, and particularly mixtures ofmuco-polysaccharides; carbohydrates; lipids; or any combination thereof.Further examples include but are not limited to, human growth hormones;bovine growth hormones; growth releasing hormones; growthhormone-releasing hormones; interferons; interleukin-1; interleukin-II;insulin; heparin, and particularly low molecular weight heparin;calcitonin; erythropoiotin; atrial naturotic factor; antigens;monoclonal antibodies; somatostatin; adrenocorticotropin, gonadotropinreleasing hormone; oxytocin; vasopressin; cromolyn sodium (sodium ordisodium chromoglycate); vancomycin; desforrioxamine (DFO); parathyroidhormone anti-microbials, including, but not limited to anti-fungalagents; or any combination thereof.

[0047] Modified Amino Acids

[0048] The terms modified amino acid, modified poly amino acid, andmodified peptide are meant to include amino acids which have beenmodified, or poly amino acids and peptides in which at least one aminoacid has been modified, by acrylating or sulfonating at least one freeamine group with an acylating or sulfonating agent which reacts with atleast one of the free amine groups present.

[0049] Amino acids, poly amino acids, and peptides, in modified form,may be used to deliver active agents including, but not limited to,biologically or chemically active agents such as for example,pharmacological and therapeutic agents.

[0050] An amino acid is any carboxylic acid having at least one freeamine group and includes naturally occurring and synthetic amino acids.

[0051] Poly amino acids are either peptides or two or more amino acidslinked by a bond formed by other groups which can be linked, e.g. anester, anhydride, or an anhydride linkage.

[0052] Peptides are two or more amino acids joined by a peptide bond.Peptides can vary in length from dipeptides with two amino acids to polypeptides with several hundred amino acids. See Chambers BiologicalDictionary, editor Peter M. B. Walker, Cambridge, England: ChambersCambridge, 1989, page 215. Special mention is made of di-peptidestri-peptides, tetra-peptides, and penta-peptides.

[0053] Although compounds I-CXXIII above have been found to act ascarriers for the oral delivery of biologically or chemically activeagents, special mention is made of compounds I-XXXI above.

[0054] Modified amino acids are typically prepared by modifying theamino acid or an ester thereof. Many of these compounds are prepared byacylation or sulfonation with agents having the formula

X—Y—R⁴

[0055] wherein: R⁴ is the appropriate radical to yield the modificationindicated in the

[0056] final product,

[0057] Y is

[0058] or SO₂, and X is a leaving group. Typical leaving groups include,but are not limited to, halogens such as, for example, chlorine,bromine, and iodine. Additionally, the corresponding anhydrides aremodifying agents.

[0059] Many of the compounds of the present invention can be readilyprepared from amino acids by methods within the skill of those in theart based upon the present disclosure. For example, compounds I-VII arederived from aminobutyric acid; Compounds VII-X and XXXII-XXXV arederived from aminocaproic acid; and Compounds XI-XXVI and XXXVI arederived from aminocaprylic acid. For example, the modified amino acidcompounds above may be prepared by reacting the single amino acid withthe appropriate modifying agent which reacts with free amino moietypresent in the amino acids to form amides. Protecting groups may be usedto avoid unwanted side reactions as would be known to those skilled, inthe art.

[0060] The amino acid can be dissolved in aqueous alkaline solution of ametal hydroxide, e.g., sodium or potassium hydroxide, and heated at atemperature ranging between about 5° C. and about 70° C., preferablybetween about 10° C. and about 40° C., for a period ranging betweenabout 1 hour and about 4 hours, preferably about 2.5 hours. The amountof alkali employed per equivalent of NH₂ groups in the amino acidgenerally ranges between about 1.25 and about 3 mmole, preferablybetween about 1.5 and about 2.25 mmole per equivalent of NH₂. The pH ofthe solution generally ranges between about 8 and about 13, preferablyranging between about 10 and about 12.

[0061] Thereafter, the appropriate amino modifying agent is added to theamino acid solution while stirring. The temperature of the mixture ismaintained at a temperature generally ranging between about 5° C. andabout 70° C., preferably between about 10° C. and about 40° C., for aperiod ranging between about 1 and about 4 hours. The amount of aminomodifying agent employed in relation to the quantity of amino acid isbased on the moles of total free NH₂ in the amino acid. In general, theamino modifying agent is employed in an amount ranging between about 0.5and about 2.5 mole equivalents, preferably between about 0.75 and about1.25 equivalents, per molar equivalent of total NH₂ group in the aminoacid.

[0062] The reaction is quenched by adjusting the pH of the mixture witha suitable acid, e.g., concentrated hydrochloric acid, until the pHreaches between about 2 and about 3. The mixture separates on standingat room temperature to form a transparent upper layer and a white oroff-white precipitate. The upper layer is discarded, and the modifiedamino acid is collected from the lower layer by filtration ordecantation. The crude modified amino acid is then dissolved in water ata pH ranging between about 9 and about 13, preferably between about 11and about 13. Insoluble materials are removed by filtration and thefiltrate is dried in vacuo. The yield of modified amino acid generallyranges between about 30 and about 60%, and usually about 45%.

[0063] If desired, amino acid esters, such as, for example benzylmethyl, or ethyl esters of amino acid compounds, may be used to preparethe modified amino acids of the invention. The amino acid ester,dissolved in a suitable organic solvent such as dimethylformamide,pyridine, or tetrahydrofuran is reacted with the appropriate aminomodifying agent at a temperature ranging between about 5° C. and about70° C., preferably about 25° C., for a period ranging between about 7and about 24 hours. The amount of amino modifying agent used relative tothe amino acid ester is the same as described above for amino acids.This reaction may be carried out acid solution, to a pH ranging betweenabout 2 and about 2.5. The modified amino acid precipitates out ofsolution and is recovered by conventional means such as filtration ordecantation. Benzyl esters may be removed by hydrogenation in an organicsolvent using a transition metal catalyst.

[0064] The modified amino acid may be purified by recrystallization orby fractionation on solid column supports. Suitable recrystallizationsolvent systems include acetonitrile, methanol and tetrahydrofuran.Fractionation may be performed on a suitable solid column supports suchas alumina, using methanol/n-propanol mixtures as the mobile phase;reverse phase column supports using trifluoroacetic acid/acetonitrilemixtures as the mobile phase; and ion exchange chromatography usingwater as the mobile phase. When anion exchange chromatography isperformed, preferably a subsequent 0-500 mM sodium chloride gradient isemployed.

[0065] In an alternate method modified amino acids having the formula

[0066] wherein Y is

[0067] or SO₂;

[0068] R¹ is C₃-C₂₄ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkyne, cycloalkyl, oraromatic;

[0069] R² is hydrogen, C₁-C₄ alkyl, or C₂-C₄ alkenyl; and

[0070] R³ is C₁-C₇ alkyl, C₃-C₁₀ cycloalkyl, aryl, thienyl, pyrrolo, orpyridyl, where R³ is optionally substituted by one or more C₁-C₅ alkylgroup, C₂-C₄ alkenyl group, F, Cl, OH, SO₂, COOH or, SO₃H; may beprepared by

[0071] (a) reacting in water and the presence of, a base a compoundhaving the formula

[0072]  R³ is C₁-C₇ alkyl, C₃-C₁₀ cycloalkyl, aryl, thienyl, pyrrolo, orpyridyl, where R³ is optionally substituted by one or more C₁-C₅ alkylgroup, C₂-C₄ alkenyl group, F, Cl, OH, SO₂, COOH or, SO₃H; may beprepared by

[0073] (a) reacting in water and the presence of a base a compoundhaving the formula

[0074] with a compound having the formula

R³—Y—X, wherein

[0075] Y, R¹, R², and R³ are as above and X is a leaving group.

[0076] Compound CXXV can be prepared, for example by the methoddescribed in Olah et al., Synthesis, 537-538 (1979).

[0077] Compound XXXI was prepared as described in Scheme I from10-undecen-1-ol, 1, by a three step procedure in an overall yield of31%. Alkylation of phthalimide with alkanol, 1, under Mitsunobuconditions, followed by reaction with hydrazine gave 1aminoundec-10-ene, 2, in 66% yield. The amine was derivatized withO-acetylsalicyloyl chloride and the resulting alkene, 3, was oxidized tothe acid using potassium permanganate. Removal of the acetate, followedby acid precipitation provided compound XXXI in 47% yield based on amine2.

[0078] Delivery Systems

[0079] The compositions of the present invention may include one or moreactive agents.

[0080] In one embodiment, compounds I-CXXIII or poly amino acids orpeptides that include at least one of these compounds may be useddirectly as a delivery carrier by simply mixing one or more compound,poly amino acid or peptide with the active agent prior toadministration.

[0081] In an alternative embodiment, the compounds poly amino acids, orpeptide may be used to form microspheres containing the active agent.These compounds, poly amino acids, or peptides are particularly usefulfor the oral administration of certain biologically-active agents, e.g.,small peptide hormones, which, by themselves, do not pass or only afraction of the administered dose passed through the gastro-intestinalmucosa and/or are susceptible to chemical cleavage by acids and enzymesin the gastrointestinal tract.

[0082] If the modified amino acids, poly amino acids, or peptides are tobe converted into microspheres, the mixture is optionally heated to atemperature ranging between about 20 and about 50° C., preferably about40° C., until the modified amino acid(s) dissolve. The final solutioncontains between from about 1 mg and to about 2000 mg of compound, polyamino acid, or peptide per mL of solution, preferably between about 1and about 500 mg per mL. The concentration of active agent in the finalsolution varies and is dependent on the required dosage for treatment.When necessary, the exact concentration can be determined by, forexample, reverse phase HPLC analysis.

[0083] When the compounds, poly amino acids, or peptides are used toprepare microspheres, another useful procedure is as follows: Compounds,poly amino acids, or peptides are dissolved in deionized water at aconcentration ranging between about 75 and about 200 mg/ml, preferablyabout 100 mg/ml at a temperature between about 25° C. and about 60° C.,preferably about 40° C. Particulate matter remaining in the solution maybe removed by conventional means such as filtration.

[0084] Thereafter, the compound, poly amino acid, or peptide solution,maintained at a temperature of about 40° C., is mixed 1:1 (V/V) with anaqueous acid solution (also at about 40° C.) having an acidconcentration ranging between about 0.05 N and about 2 N, preferablyabout 1.7 N. The resulting mixture is further incubated at 40° C. for aperiod of time effective for microsphere formation, as observed by lightmicroscopy. In practicing this invention, the preferred order ofaddition is to add the compound, poly amino acid, or peptide solution tothe aqueous acid solution.

[0085] Suitable acids for microsphere formation include any acid whichdoes not

[0086] (a) adversely effect the modified amino acids, poly amino acids,or peptides e.g., initiate or propagate chemical decomposition;

[0087] (b) interfere with microsphere formation;

[0088] (c) interfere with microsphere incorporation of the active agentcargo, and

[0089] (d) adversely interact with the active agent cargo.

[0090] Preferred acids for use in this aspect include acetic acid,citric acid, hydrochloric acid, phosphoric acid, malic acid and maleicacid.

[0091] A microsphere stabilizing additive may be incorporated into theaqueous acid solution or into the compound or cargo solution prior tothe microsphere formation process. With some active agents the presenceof such additives promotes the stability and/or dispersibility of themicrospheres in solution.

[0092] The stabilizing additives may be employed at a concentrationranging between about 0.1 and 5% (w/v), preferably about 0.5% (w/v).Suitable, but non-limiting, examples of microsphere stabilizingadditives include gum acacia, gelatin, methyl cellulose, polyethyleneglycol, polypropylene glycol, carboxylic acids and salts thereof, andpolylysine. The preferred stabilizing additives are gum acacia, gelatinand methyl cellulose.

[0093] Under the above conditions, the compound molecules, poly aminoacids, or peptides form hollow or solid matrix type microspheres whereinthe cargo is distributed in a carrier matrix or capsule typemicrospheres encapsulating liquid or solid cargo. If the compound, polyamino acid, or peptide microspheres are formed in the presence of asoluble material, e.g., a pharmaceutical agent in the aforementionedaqueous acid solution, this material will be encapsulated within themicrospheres. In this way, one can encapsulate pharmacologically activematerials such as peptides, proteins, and polysaccharides as well ascharged organic molecules, e.g., antimicrobial agents, which normallyhave poor bioavailability by the oral route. The amount ofpharmaceutical agent which may be incorporated by the microsphere isdependent on a number of factors which include the concentration ofagent in the solution, as well as the affinity of the, cargo for thecarrier. The compound, poly amino acid, or peptide microspheres do notalter the physiological and biological properties of the active agent.Furthermore, the encapsulation process does not alter thepharmacological properties of the active agent. Any pharmacologicalagent can be incorporated within the microspheres. The system isparticularly advantageous for delivering chemical or biological agentswhich otherwise would be destroyed or rendered less effective byconditions encountered within the body of the animal to which it isadministered, before the microsphere reaches its target zone (i.e., thearea in which the contents of the microsphere are to be released) andfor delivering pharmacological agents which are poorly absorbed in thegastro-intestinal tract. The target zones can vary depending upon thedrug employed.

[0094] The particle size of the microsphere plays an important role indetermining release of the active agent in the targeted area of thegastro-intestinal tract. The preferred microspheres have diametersbetween about ≦0.1 microns and about 10 microns, preferably betweenabout 0.5 microns and about 5 microns. The microspheres are sufficientlysmall to release effectively the active agent at the targeted areawithin the gastrointestinal tract such as, for example, between thestomach and the jejunum. Small microspheres can also be administeredparenterally by being suspended in an appropriate carrier fluid (e.g.,isotonic saline) and injected directly into the circulatory system,intramuscularly, or subcutaneously. The mode of administration selectedwill vary, of course, depending upon the requirement of the active agentbeing administered. Large amino acid microspheres (>50 microns) tend tobe less effective as oral delivery systems.

[0095] The size of the microspheres formed by contacting compounds, polyamino acids, or peptides with water or an aqueous solution containingactive agents can be controlled by manipulating a variety, of physicalor chemical parameters, such as the pH, osmolarity or ionic strength ofthe encapsulating solution, size of the ions in solution and by thechoice of acid used in the encapsulating process.

[0096] The administration mixtures are prepared by mixing an aqueoussolution of the carrier with an aqueous solution of the activeingredient, just prior to administration. Alternatively, the carrier andthe biologically or chemically active ingredient can be admixed duringthe manufacturing process. The solutions may optionally containadditives such as phosphate buffer salts, citric acid, acetic acid,gelatin, and gum acacia.

[0097] Stabilizing additives may be incorporated into the carriersolution. With some drugs, the presence of such additives promotes thestability and dispersibility of the agent in solution.

[0098] The stabilizing additives may be employed at a concentrationranging between about 0.1 and 5% (W/V), preferably about 0.5% (W/V).Suitable, but non-limiting, examples of stabilizing additives includegum acacia, gelatin, methyl cellulose, polyethylene glycol, carboxylicacids and salts thereof, and polylysine. The preferred stabilizingadditives are gum acacia, gelatin and methyl cellulose.

[0099] The amount of active agent is an amount effective to accomplishthe purpose of the particular active agent. The amount in thecomposition typically is a pharmacologically or biologically effectiveamount. However, the amount can be less than a pharmacologically orbiologically effective amount when the composition is used in a dosageunit form, such as a capsule, a tablet or a liquid, because the dosageunit form may contain a multiplicity of carrier/biologically, orchemically active agent compositions or may contain a dividedpharmacologically or biologically effective amount. The total effectiveamounts can then be administered in cumulative units containing, intotal, pharmacologically or biologically or chemically active amounts ofbiologically or pharmacologically active agent.

[0100] The total amount of active agent, and particularly biologicallyor chemically active agent, to be used can be determined by thoseskilled in the art. However, it has surprisingly been found that withsome biologically or chemically active agents, the use of the presentlydisclosed carriers provides extremely efficient delivery, particularlyin oral, intranasal, sublingual, intraduodenal, or subcutaneous systems.Therefore, lower amounts of biologically or chemically active agent thanthose used in prior dosage unit forms or delivery systems can beadministered to the subject, while still achieving the same blood levelsand therapeutic effects.

[0101] The amount of carrier in the present composition is a deliveryeffective amount and can be determined for any particular carrier orbiologically or chemically active agent by methods known to thoseskilled in the art.

[0102] Dosage unit forms can also include any of excipients; diluents;disintegrants; lubricants; plasticizers; colorants; and dosing vehicles,including, but not limited to water, 1,2-propane diol, ethanol, oliveoil, or any combination thereof.

[0103] Administration of the present compositions or dosage unit formspreferably is oral or by intraduodenal injection.

[0104] The delivery compositions of the present invention may alsoinclude one or more enzyme inhibitors. Such enzyme inhibitors include,but are not limited to, compounds such as actinonin or epiactinonin andderivatives thereof. These compounds have the formulas below:

[0105] Derivatives of these compounds are disclosed in U.S. Pat. No.5,206,384. Actinonin derivatives have the formula:

[0106] wherein R⁵ is sulfoxymethyl or carboxyl or a substituted carboxygroup selected from carboxamide, hydroxyaminocarbonyl and alkoxycarbonylgroups; and R⁶ is hydroxyl, alkoxy hydroxyamino or sulfoxyamino group.Other enzyme inhibitors include, but are not limited to, aprotinin(Trasylol) and Bowman-Birk inhibitor.

[0107] The compounds and compositions of the subject invention areuseful for administering biologically or chemically active agents to anyanimals such as birds; mammals such as primates and particularly humans;and insects. The system is particularly advantageous for deliveringchemically or biologically or chemically active agents which wouldotherwise be destroyed or rendered less effective by conditionsencountered before the, active agent its target zone (i.e. the area inwhich the active agent, of the delivery composition are to be released)and within the body of the animal to which they are administered.Particularly the compounds an compositions of the present invention areuseful in orally administering active agents, especially those which arenot ordinarily orally deliverable.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0108] The following examples illustrate the invention withoutlimitation. All parts are given by weight unless otherwise indicated.

EXAMPLE 1

[0109] Compound XIX was prepared as follows:

[0110] A 3 L three-neck round bottom flask was fitted with an overheadmechanical stirrer and a thermometer, and the flask was cooled in anice-bath. A solution of 8-aminocaprylic acid (100.0 g, 0.65 moles) in 2M aqueous sodium hydroxide (1.4 L) was charged into the round bottomflask. The temperature of the solution was kept at about 5° C., andO-acetylsalicyloyl chloride (198.6 g, 0.76 moles, 1.2 equiv.) was addedportionwise over 7 hours. The mixture was stirred at 5° C. for 12 hoursto yield a yellow homogenous solution. The solution was acidified with 1M hydrochloric acid to pH 6.8, and was extracted with ethyl acetate(2×600 mL). The pH of the aqueous layer was readjusted to 6.3 and wasfurther extracted with ethyl acetate (2×600 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered, and evaporatedunder reduced pressure. The residue was redissolved in a minimum volumeof 2 M aqueous sodium hydroxide, and the, pH of the solution was between9.5 and 10. The mixture was acidified with stirring with 1 Mhydrochloric acid to pH of about 6.2, and a solid was formed. The solidwas filtered, washed with water (3×300 mL), and recrystallized from 55%methanol/water (v/v) to yield; Compound XVIII as an off-white solid(99.7 g, 57%).

[0111] Properties are listed below.

[0112] Mp 116-117° C. ¹H NMR (300 MHz, DMSO-d₆) δ: 12.70 (1H; br s),11.95 (1H; br s) 8.81 (1H, t), 7.82 (1H, m), 7.38 (1H, m), 6.84 (2H, m),2.36 (2H, q), 2.18 (2H, t), 1.50 (4H, br m), 1.28 (6H, m), Anal. Calcdfor C₁₅H₂₁NO₄: C, 64.50; H, 7.58; I N, 5.02. Found: C, 64.26; H, 7.81;N, 4.93.

[0113] Similar procedures were used to prepare Compounds I, II, III, IV,VI, IX, X, XI, XII, XIII, XIV, XX, XXI, XXIII, XXVII, XXVIII, XXXIII,and XXXIV.

[0114] Properties are listed below.

[0115] Compound I: ¹H NMR (300 MHz, D₂O): δ 1:5 (2H, m) 2.0 (2H, t) 2.3(2H,t) 7.5 (2H t) 7.6 (1H, m) 7.3 (2H, m)

[0116] Compound II: ¹H NMR (300 MHz, D₂O): δ 1.4 (8H, m) 1.7 (6H, m) 2.1(2H,t) 1.25 (1H, m) 3.05 (2H, t)

[0117] Compound III: ¹H NMR (300 MHz, DMSO-d₆): δ0.7 (3H, m) 0.9 (2H, m)1.1 (3H,q) 1.6 (5H, m) 1.75 (2H, q) 2.1 (2H, t) 3.0 (2 h, q) 7.9 (1H, m)

[0118] Compound IV: Anal. Calcd for C₁₁H₁₃NO₄: C 59.9, H, 5.87. N, 6.27Found: C 58.89, H, 58.5, N 6.07 ¹H NMR (300 MHz, DMSO-d₆):δ 1.8 (2H, m)2.3 (2H,t) 3.1 (2H,q) 6.9 (2H, t) 7.4, (1H, t) 7.8 (1H, d) 8.85 (1H, t).12.0 (1H, s) 12.15 (1H, s)

[0119] Compound VI: ¹H NMR (300 MHz, D₂O): δ 0.8 (2H, m). 1.1 (4H, m)1.4 (2H,q) 1.6 (7H, m) 2.15 (4H, m) 3.1 (2H, t)

[0120] Compound IX: ¹H NMR (300 MHz, DMSO-d₆): δ 0.9 (q, 3H), 1.2 (m,7H), 1.3 (q, 2H), 1.5 (q, 3H), 1.9 (d 2H), 2.0 (d, 1H), 2.2 (t, 2H), 3.0(q, 3H), 7.7 (s, 1H)

[0121] Compound X: ¹H NMR (300 MHz, DMSO-d₆): δ 0.7 (d, 2H), 0.9 (dd,1H), 1.2-1.3 (m, 7H), 1.5 (q, 3H), 1.6-1.8 (m, 5H), 2.15 (t, 2H), 3.0(m, 3H), 7.5 (s, 1H), 12.0 (s, 1H)

[0122] Compound XI: Anal. Calcd for C₁₅H₂₀NO₃Cl: C, 60.48, H, 6.78, N,4.70 Found: C, 60.4, H. 6.68, N, 4.53. ¹H NMR (300 MHz, DMSO-d₆): δ 1.28(m, 6H) 1.48 (m, 4H) 2.19 (t, 2H) 3.19 (qt, 2H), 7.323-7.48 (m, 4H), 839(t, H), 12.09 (s, 1H)

[0123] Compound XII: Anal. Calcd for C₁₇H₂₂NO₃: C, 66.42, H, 7.23, N,4.56 Found: C, 65.80, H, 7.17, N, 4.14. ¹H NMR (300 MHz, DMSO-d₆): δ1.25 (m, 6H) 1.43-1.49 (m, 4H) 2.18 (t. 2H) 3.15 (qt, 2H), 6.72 (d, 1H),7.21-7.26 (m, 2H), 7.39 (t, 1H), 7.48 (d, 1H), 7.65 (t, 1H), 8.21 (t,1H)

[0124] Compound XIII: Anal. Calcd for C₁₅H₁₉NO₃: C, 60.18, H, 6.41, N,4.67 Found: C, 60.26, H, 6.53, N, 4.61. ¹H NMR (300 MHz, DMSO-d₆): δ1.28 (m, 6H), 1.45-1.52 (m, 4H), 2.19 (t, 2H), 2.22 (qt, 2H), 7.13 (m,2H), 7.43-7.53 (m, 1H), 8.67 (t, 1H) 12.03 (s, 1H)

[0125] Compound XIV: Anal. Calcd for C₁₄H₂₀N₂O₃: 0.66 H₂O: C, 63.04, H,7.91, N, 10.34 Found: O, 63.21, 7.59, 10.53 ¹H NMR (300 MHz, DMSO-d₆): δ1.22-12.8 (m, 6H), 1.48-1.50 (m, 4H), 2.18 (t, 2H), 3.24 (qt, 2H), 7.48(m, 1H), 8.15 (d, 1H), 8.63-8.69 (m, 2H), 8.97 (d, 1H)

[0126] Compound XX: Anal. Calcd for C₁₅H₂₀NO₃F: C, 60.09, H, 7.19, N,4.98 Found: C, 63.82, H, 7.23, N, 4.94. ¹H NMR (300 MHz, DMSO-d₆): δ1.28 (m, 6H) 1.49 (m, 4H) 2.19 (t, 2H) 3.23 (qt,

[0127] Compound XXXI: ¹H NMR (300 MHz, DMSO-d₆): δ 1.24 (10H br m), 1.51(4H, m), 2.17 (2H, t), 3.27 (2H, m), 6.86 (2H, m), 7.37 (1H, m), 7.82(1H, m), 8.80 (1H, t), 11.95 (1H, s), 12.72 (1H, s).

[0128] Compound XXXIII: ¹H NMR (300 MHz, DMSO-d₆): δ 1.2 (a, 2H), 1.3(q,2H), 1.3 (q, 2H), 1.5 (q, 2H), 2.2 (t, 2H) 3.0 (q, 2H), 3.5 (s, 2H),7.3 (m, 5H), 8.0 (s, 1H)

[0129] Compound XXXIV: Anal. Calcd, for C₁₂H₁₇NO₄: C, 62.23, H, 6.83, N,5.57 Found: C, 61.93, H, 6.80, N, 5.56. ¹H NMR (300 MHz, DMSO-d₆): δ1.24-1.34 (m, 2H) 1.49-1.57 (m, 4H) 2.19 (t, 2H) 3.26 (qt, 2H), 6.68,(t, 2H), 7.37 (s, 1H), 7.83 (d, 1H) 8.81 (t, 1H), 12.08 (s, 1H), 12.72(s, 1H)

EXAMPLE 1A

[0130] An alternate synthesis of compound XIX was as follows:

[0131] A 5 L three-neck round bottom flask was fitted with a heatingmantle, an overhead mechanical stirrer, an addition funnel, and athermometer. The reaction was performed under an argon atmosphere.Hydroxylamine-O-sulfonic acid (196.7 g, 1.74 moles, 1.10 equiv.) andformic acid (1 L) were charged into the round bottom flask and, stirredto form a white slurry. A solution of cyclooctanone (200.0 g 1.58 moles,1.0 equiv.) in formic acid (600 mL) was added dropwise to the whiteslurry via the addition funnel. After the addition, the addition funnelwas replaced by a reflux condenser, and the reaction was heated toreflux (internal temperature about 105° C.) for 1 hour to give a brownsolution. After the solution was cooled to room temperature, it waspoured into a mixture of saturated aqueous ammonium chloride (1.5 L) and

[0132] Compound XXXIII: ¹H NMR (300 MHz, DMSO-d₆): δ 1.2 (a, 2H), 1.3(q, 2H), 1.3 (q, 2H), 1.5 (q, 2H), 2.2 (t, 2H), 3.0 (q, 2H), 3.5 (s, 2H)7.3 (m, 5H), 8.0 (s, 1H)

[0133] Compound XXXIV: Anal. Calcd for C₁₂H₁₇NO₄: C, 62.23, H 6.83, N,5.57 Found: C, 61.93, H, 6.80, N, 5.56. ¹H NMR (300 MHz, DMSO-d₆): δ1.24-1.34 (m, 2H) 1.49 1.57 (m, 4H) 2.19 (t, 2H) 3.26 (qt, 2H), 6.68 (t,2H), 7.37 (s, 1H), 7.83 (d, 1H) 8.81 (t, 1H), 12.08 (s, 1H), 12.72 (s,1H)

EXAMPLE 1A

[0134] An alternate synthesis of compound XIX was as follows:

[0135] A 5-L three-neck round bottom flask was fitted with a heatingmantle, an overhead mechanical stirrer, an addition funnel, and athermometer. The reaction was performed under an argon atmosphere.Hydroxylamine-O-sulfonic acid (196.7 g, 1.74 moles, 1.10 equiv.) andformic acid (1 L) were charged into the round bottom flask and stirredto form a white slurry. A solution of cyclooctanone (200.0 g 1.58 moles,1.0 equiv.) in formic acid (600 mL) was added dropwise to the whiteslurry via the addition funnel. After the addition, the addition funnelwas replaced by a reflux condenser, and the reaction was heated toreflux (internal temperature about 105° C.) for 1 hour to give a brownsolution. After the solution was cooled to room temperature, it waspoured into a mixture of saturated aqueous ammonium chloride (1.5 L) andwater (1.5 L). The aqueous mixture was extracted with chloroform (3×1200mL). The combined chloroform layers were transferred into a breaker, andsaturated sodium bicarbonate (2 L) was added slowly. The chloroformlayer was then separated, dried over anhydrous sodium sulfate, andevaporated under reduced pressure to afford a brown oil. The oil wasplaced in a 500 mL round bottom flask with a magnetic stirrer. The roundbottom flask was placed in a silicon oil bath and was fitted with ashort path vacuum distillation head equipped with a thermometer. ACow-type receiver was connected to three 250 mL flasks.2-Azacyclononanone (145 g, 65%, mp 64-69° C.) was obtained by vacuumdistillation (fraction with head temperature range from 80 to 120° C. atpressures between 3.0 and 3.4 mmHg).

[0136] A 5 L three-neck round bottom flask was fitted with a heatingmantle, an overhead mechanical stirrer, a reflux condenser, and a 29thermometer. A suspension of 2-azacyclononanone (83 g, 0.59 moles, 1.0equiv.) in 5M aqueous sodium hydroxide (650 mL, 3.23 moles, 5.5 equiv.)was charged into the round bottom flask. The mixture was heated toreflux (internal-temperature about 110° C.) for 4 hours to yield a clearyellow solution. The heating mantle and reflux condenser were removed.After the solution cooled to room temperature, it was diluted with water(650 mL) and cooled further in an ice bath. Finely-groundO-acetylsalicyloyl chloride (114.7 g, 0.59 moles, 1.0 equiv.) was addedportionwise to the solution with stirring and continued cooling over 1hour. After an additional 30 minutes, the ice-bath was removed andstirring was continued at ambient temperature for 21 hours to give abrownish yellow solution. The stirred mixture was acidified with 2-Msulfuric acid (about 850 mL) to a pH of about 1, and a yellow solid wasformed. The solid was collected by filtration and was dissolved in warmmethanol (1.7 L). Activated charcoal (about 5 g) was added to themethanol and the solution was stirred for 10 minutes. The activatedcharcoal was removed by filtration, and the charcoal residue was washedwith additional 300 mL methanol. Water (2 L) was added to the combinedfiltrates (i.e. the 2 L methanol), and an off-white solid precipitatedupon standing at 4° C. overnight. The crude product was filtered and wasrecrystallized from 65% methanol/water (v/v) to yield Compound XIX (69.1g, 42%) as off-white solid.

[0137] Properties are listed below:

[0138] mp 116-117° C.; HPLC, ¹H NMR and Anal. Calcd for C₁₅H₂₁NO₄: C,64.50; H, 7.58; N, 5.02. Found: C, 64.26; H, 7.81; N, 4.93.

[0139]¹H NMR (300 MHz, DMSO-d₆): δ 12.1 (1H, br), 7.8 (1H, dd), 7.6 (3H,m), 7.4 (1H, m), 7.3 (2H, m), 7.1 (1H, d), 7.0 (1H, t), 6.9 (1H, d), 3.9(3H, s), 2.8 (2H, t), 2.5 (4H, m).

[0140] Anal. Calcd for C₁₉H₁₉NO₄: C, 70.14; H, 5.88; N, 4.31. Found: C,69.76; H, 5.91; N, 4.21.

EXAMPLE 4

[0141] Compound CXVII was prepared as follows:

[0142] A 3 L three-neck round bottom flask was fitted with an overheadmechanical stirrer and a thermometer. A solution of 8-aminocaprylic acid(10.0 g, 0054 moles) in 2 M aqueous sodium hydroxide (1.4 L) was chargedinto the round bottom flask and O-nitrobenzoyl chloride (12.0 g, 0.065moles, 1.2 equiv.) was added portionwise over 7 h. The mixture wasstirred at 25° C. for 12 h to afford a yellow homogenous solution. Thesolution was acidified with 1 M hydrochloric acid to about pH 2, an oilyresidue separated and was decanted. The oil was dissolved in stirredwater (300 mL) and cooled in and ice/water bath. The productprecipitated as a white solid. The solid was filtered, washed with water(3×300 mL), and recrystallized from 55% acetonitrile/water (v/v) toprovide Compound CXVII as an off-white solid (7.4 g, 47%). mp 89-92° C.

[0143] Properties are listed below.

[0144]¹H NMR (300 MHz, DMSO-d₆) δ: 12.0 (1H, s), 8.65 (1H, t), 8.0 (1H,dd), 7.8 (1H, m), 7.65 (1H, m), 7.5 (1H, m), 3.2 (2H, q), 2.2 (2H, t),1.5 (4H, br m), 1.3 (6H, br m).

[0145] Anal. Calcd for C₁₅H₂₀N₂O₅: C, 58.41; H, 6.54; N, 9.09. Found: C,58.50; H, 6.71; N, 9.14.

[0146] The other compounds of the invention can be readily prepared byfollowing the procedures described in Examples 1-4.

[0147] added via syringe. The ice bath was removed and the reaction wasstirred at room temperature for 3.5 hours. After removal of the solvent,the residue was dissolved in EtOAc (50 mL) and washed with water (2×30mL). The organic layer was dried and evaporated to afford1-(O-acetylsalicyloylamino)undec-10-ene as a colorless oil, in aquantitative yield, 6.59 g.

[0148] Properties are listed below.

[0149]¹H NMR (300 mHz, DMSO-d₆: δ1.26 (12H, br s), 1.47 (2H,m),1.99(2H,m), 2.19 (3H,s), 3.15 (2H, q), 4.95 (2H, m), 5.78 (1H, m), 7.15(1H, m), 7.30 (1H, m), 7.50 (2H, m) 8.24 (1H, t).

[0150] Compound XXXI

[0151] 1-(O-Acetylsalicyloylamino)under-10-ene (6.59 g, 19.25 mmol, 1equiv) in dichloromethane (108 mL) was added to a mixture of water (108mL), sulfuric acid (9M, 13 mL), glacial acetic acid (2.16 mL) andmethyltrialkyl(C₈-C₁₀) ammonium chloride (0.32 g) (Adogen® 464,available from Aldrich Chemical Co.). The mixture was stirred vigorouslyin an ice bath and potassium permanganate (9.13 g, 57.75 mmol, 3 equiv)was added in portions over 1.5 hours. After the addition, the ice bathwas removed and the resultant purple solution was stirred at roomtemperature for 20 hours. The solution was cooled in an ice bath andsodium bisulfite (6.8 g) was added to dissipate the excess permanganate.The organic layer was separated and the aqueous layer was extracted withethyl acetate (2×50 mL). The combined organic layers were washed withbrine (50 mL), dried and evaporated. Sodium hydroxide (2M, 50 mL, wasadded to the residue and stirred for 30 min. The solution was dilutedwith water (50 mL), washed with ether (50 mL) and acidified to pH 1 with2M hydrochloric acid. A solid formed and was collected by filtration.Recrystallization of the solid from 65% MeOH/H₂O gave XXXI as a tansolid (2.78 g, 47% based on the amine).

[0152] Properties are listed below.

[0153]¹H NMR (300 mHz, DMSO-d₆): δ1.24 (10H, br m), 1.51 (4H, m), 2.17(2H, t), 3.27 (2H, m), 6.86 (2H, m), 7.37 (1H m), 7.82 (1H, m), 8.80(1H, t), 11.95 (1H, s), 12.72 (1H, s).

EXAMPLE 3

[0154] Compound LXXXVI was prepared as follows:

[0155] A one liter three-neck round bottom flask was fitted with amagnetic stirrer and a condenser. A solution of3-(4-aminophenyl)propionic acid (30 g, 0.182 moles) in methylenechloride (300) mL) was charged to the flask and trimethylsilyl chloride(46.2 mL, 0.364 moles) was added in one portion. The reaction mixturewas refluxed for 1.5 hours, allowed to cool to room temperature, andthen immersed in an ice/water bath. Triethylamine (76.2 mL, 0.546 moles)was added, followed by 2-methoxycinnamoyl chloride (35.8 g, 0.182moles). The reaction mixture was allowed to warm to room temperature andthen stirred for 48 hours. The solvent was removed by rotary evaporationand saturated sodium bicarbonate solution and ethyl acetate were addedto the residue. The layers were separated, the aqueous layer was,acidified to pH 1.4 with 2N aqueous sulfuric acid and extracted withethyl acetate (2×400 mL). The combined organic extracts wereconcentrated in vacuo and the residue recrystallized from 50% (v/v)aqueous methanol to provide the product as a tan solid (48.57 g, 82%).

[0156] Properties are listed below.,

[0157]¹H NMR (300 MHz, DMSO-d₆) δ 12.1 (1H, br), 7.8 (1H, dd), 7.6 (3H,m), 7.4 (1H, m), 7.3 (2H, m), 7.1 (1H, d), 7.0 (1H, t), 6.9 (1H, d), 3.9(3H, s), 2.8 (2H, t), 2.5 (4H, m).

[0158] Anal. Calcd for C₁₉H₁₉NO₄: C, 70.14; H, 5.88; N, 4.31. Found: C,69.76; H, 5.91; N, 4.21.

EXAMPLE 4

[0159] Compound CXVII was prepared as follows:

[0160] A 3 L three-neck round bottom flask was fitted with an overheadmechanical stirrer and a thermometer. A solution of 8-aminocaprylic acid(10.0 g, 0.054 moles) in 2 M aqueous sodium hydroxide (1.4 L) wascharged into the round bottom flask and O-nitrobenzoyl chloride (12.0 g,0.065 moles, 1.2 equiv.) was added portionwise over 7 h. The mixture wasstirred at 25° C. for 12 h to afford a yellow homogenous solution. Thesolution was acidified with 1 M hydrochloric acid to about pH 2, an oilyresidue separated and was decanted. The oil was dissolved was stirredwater (300 mL) and cooled in and ice/water bath. The productprecipitated as a white solid. The solid was filtered, washed with water(3×300 mL), and recrystallized from 55% acetonitrile/water (v/v) toprovide Compound CXVII as an off-white solid (7.4 g, 47%). mp 89-92° C.

[0161] Properties are listed below.

[0162]¹H NMR (300 MHz, DMSO-d₆) δ: 12.0 (1H, s), 8.65 (1H, t), 8.0 (1H,dd), 7.8 (1H, m), 7.65 (1H, m), 7.5 (1H, m), 3.2 (2H, q), 2.2 (2H, t)1.5 (4H, br m), 1.3 (6H, br m).

[0163] Anal. Calcd for C₁₅H₂₀N₂O₅: C, 58.41: H, 6.54; N, 9.09 Found: C,58.50; H, 6.71; N, 9.14.

[0164] The other compounds of the invention can be readily prepared byfollowing the procedures described in Examples 14.

EXAMPLES 5-15 In Vivo Evaluation of Recombinant Growth Hormone in Rats

[0165] Dosing compositions were prepared by mixing the modified aminoacids and recombinant human growth hormone (rhGH) as listed in Table 1below in, a phosphate buffer solution at a pH of about 7-8.

[0166] Rats were administered the dosing composition by sublingual, oralgavage, intraduodenal administration, or colonic administration.Delivery was evaluated by using an ELISA assay for rhGH from MedixBiotech, Inc. For intracolonic administration, a sample was prepared anddosed to fasted rats at 25 mg/kg of carrier in a buffered solutioncontaining propylene glycol (0-5.0%) and 1 mg/kg rhGH.

[0167] Results are illustrated in Table 1 below.

COMPARATIVE EXAMPLE 5A

[0168] rhGH (6 mg/ml) was administered by oral gavage to a rat, anddelivery was evaluated according to the procedure of Example 5.

[0169] Results are illustrated in Table 1 below. TABLE 1 In VivoDelivery of rhGH Carrier Drug Mean Peak Serum Exam- Dose Dose Method ofLevels of rhGH ple Carrier (mg/kg) (mg/kg) Administration (ng/mL) 5 I500 6 oral  26.6 +/− 43.83 5A none 0 6 oral   <10 +/− 10 6 V 500 6 oral 3.22 +/− 7.2 7 VI 500 6 oral  19.34 +/− 18.73 8 VIII 500 6 oral  73.41+/− 70.3 9 IX 500 6 oral  28.70 +/− 41.7 10 XIII 25 1 colonic 109.52 +/−36.1 11 XIX 200 3 oral  60.92 +/− 26.3 12 XIX 25 1 colonic 111.52 +/−16.4 13 XIX 100 3 sublingual 119.14 +/− 65.6 14 XIX 25 1 intranasal 92.7 +/− 73.2 15 XXVII 25 1 colonic  73.72 +/− 4.9

EXAMPLES 16-27 In Vivo Evaluation of Recombinant Growth Hormone in Rats

[0170] Preparation of Dosing Solutions

[0171] The deliver agents reconstituted with distilled water andadjusted to pH 7.2-8.0 with either aqueous hydrochloric acid or aqueoussodium hydroxide. A stock solution of rhGH was prepared by mixing rhGH,D-mannitol and glycine and dissolving this mixture in 2% glycerol/water.The stock solution was then added to the delivery agent solution.Several delivery agent to active agent ratios, were studied.

[0172] In Vivo Experiments.

[0173] Male Sprague-Dawley rats weighing 200-250 g were fasted for 24hours and administered ketamine (44 mg/kg) and chlorpromazine (1.5mg/kg) 15 minutes prior to dosing. The rats were administered one of thedosing solutions described above by subcutaneous injection, intranasalinstillation, or sublingual instillation. Blood samples were collectedserially from the tail artery for serum calcium concentrationdetermination or serum rhGH concentrations. The dose of rhGHadministered in these experiments was 0.1 mg/kg.

[0174] Serum rhGH concentrations were quantified by an rhGH enzymeimmunoassay test kit. The results are given in Table 2 and FIGS. 1 and2.

[0175] In FIG. 2 the circles represent the response following SL dosingof an aqueous solution of compound CXXIII and rhGH. The squaresrepresent the response following IN dosing of an aqueous solution ofcompound CXXIII and rhGH. The triangles represent the response followingIC dosing of an aqueous solution of compound CXXIII and rhGH. The doseof compound CXXIII was 25 mg/kg and the dose of rhGH was 1 mg/kg.

COMPARATIVE EXAMPLE 16A

[0176] rhGH (1 mg/kg) was administered by oral gavage to a rat, anddelivery was evaluated according to the procecure of Example 16.

[0177] Results are illustrated in Table 2 below. TABLE 2 Delivery AgentEnhancement of Recombinant Human Growth Hormone (rhGH) BioavailabilityAdministered by Subcutaneous Administration. Delivery Agent Dose PeakSerum [rhGH] Example Deliver Ageny (mg/kg) (ng/mL) 16 CXXIII 1.0 22 ± 3 16A None 0.0  4 ± 2 17 CXXIII 2.5 25 ± 5 18 CXXIII 25 30 ± 6 19 CXI 2.516 ± 2 20 LVIII 1.0  29 ± 10 21 LXXXVI 1.0 22 ± 7 22 LXXXVI 2.5 23 ± 523 LXI 2.5 26 ± 5 24 CX 1.0 15 ± 3 25 CXV 1.0 25 ± 3 26 LXVI 1.0 33 ± 527 CIX 1.0 16 ± 3

EXAMPLES 28-33 In Vivo Evaluation of Interferon in Rats

[0178] Dosing compositions were prepared by mixing the modified aminoacid compounds and interferon α2b as listed in Table 3 below in aTrizmo® hydrochloride buffer solution, (Tris-HCl) at a pH of about 7-8.Propylene, glycol (0-25%) was added as a solubilizing agent, ifnecessary.

[0179] Rats were administered the do sing composition by oral gavage,intraduodenal administration, or intracolonic administration. Deliverywas evaluated by use of an ELISA assay for human interferon a fromBiosource, Inc.

[0180] Results of intracolonic administration are illustrated, in Table3 below.

COMPARATIVE EXAMPLE 28A

[0181] Interferon α2b (250 μg/kg) was administered intracolonically torats, and delivery was evaluated according to the procedure of Example14.

[0182] Results are illustrated in Table 3 below. TABLE 3 In VivoDelivery of Interferon by Intracolonic Administration Mean Peak SerumCarrier Dose Interferon Dose Levels of Interferon Example Carrier(mg/kg) (μg/kg) (pg/mL) 28 VII 100 250 5241 +/− 2205  28A none  0 250 029 XI 100 250 1189 +/− 1373 30 XII 100 250 6955 +/− 2163 31 XIX 100 25011193 +/− 8559  32 XXI 100 250 4238 +/− 2789 33 XXXIV 100 250 4853 +/−5231

[0183] Results are illustrated in Table 4 below.

EXAMPLES 34-37 In Vivo Evaluation of Salmon Calculation in Rats

[0184] Dosing compositions were prepared by mixing the modified aminoacids and salmon calcitonin as listed in Table 4 below 400 mg of carrierwere added to 2.9 mL of 25% aqueous propylene glycol. The resultantsolution was stirred and the pH was adjusted to 7.2 with sodiumhydroxide (1.0 N). Water was added to bring the total volume to 2.0 mL.The sample had a final carrier concentration of 200 mg/mL. Calcitonin(10 μg) was added, to the solution. The total calcitonin concentrationwas 2.5 μg/mL.

[0185] For each sample a group of fasted rats were anesthetized. Therats were administered the dosing composition by oral gavageintracolonic instillation, or intraduodenal administration. Bloodsamples were collected serially from the tall artery. Serum calcium wasdetermined by testing with a Calcium Kit (Sigma Chemical Company, St.Louis, Mo., USA).

[0186] Results are illustrated in Table 4, below. TABLE 4 In VivoDelivery of Calcitonin Maximum Decrease in Carrier Drug Serum CalciumExam- Dose Dose Method of (% below ple Carrier (mg/kg) (μg/kg)Administration baseline) 34 I 400 10 oral 35 V 400 10 oral 18.35 +/−2.87 36 XIX 10 3 intracolonic 26.49 +/− 12.3 37 XIX 200 7.5 oral 25.48+/− 4.7

EXAMPLES 38-43 In Vivo Evaluation of Salmon Calcitonin in Rats

[0187] Preparation of Dosing Solution.

[0188] The delivery agents were reconstituted with distilled water andadjusted to pH 7.2-8.0 with either aqueous hydrochloric acid or aqueoussodium hydroxide. A stock solution of sCT was prepared by dissolving sCTin citric acid (0.685N). The stock solution was then added to thedelivery agent solution. Several different delivery agent to activeagent ratios were studied.

[0189] In Vivo Experiments.

[0190] Male Sprague-Dawley, rats weighing 200-250 g were fasted for 24hours and administered ketamine (44 mg/kg) and chlorpromazine (1.5mg/kg) 15 minutes prior to dosing. The rats were administered one of thedosing solutions described above by subcutaneous injection. Bloodsamples were collected serially from the tail artery for serum calciumconcentration.

[0191] Serum calcium concentrations were quantified by theo-cresolphthalein complexone method (Sigma) using a UV/VISspectrophotometer (Perkin Elmer). The results are given in Table 5.

EXAMPLES 38A

[0192] Salmon calcitonin was administered by oral gavage to rats, anddelivery was evaluated according to the Procedure of Example 38. Theresults are given in Table 5 below. TABLE 5 Delivery Agent Enhancementof Salmon Calcitonin (sCT, dosed at 0.2 μg/kg) BioavailabilityAdministered by Subcutaneous Administration. Delivery Agent Dose PercentDecrease in Example Deliver Ageny (μg/kg) Serum Calcium 38 CXXIII 2 17 ±3  38A None 0 17 ± 2 39 CXXIII 20 25 ± 4 40 CXXIII 200 25 ± 5 41 CXXIII2000 26 ± 5 42 CXI 20 21 ± 4 43 CXIV 20 20 ± 3

EXAMPLES 44-50 In Vivo Evaluation of Heparin in Rats

[0193] Dosing compositions were prepared by mixing the modified aminoacids and heparin as listed in Table 4. In a test tube, 900 mg ofcarrier were dissolved in 3 mL of propylene glycol, and 0.299 g ofsodium heparin was dissolved in 3 mL of water. The solutions were mixedby vortex. Sodium hydroxide (10M) was added to the resulting mixtureuntil a solution was obtained. The pH was then adjusted to 7.4+/−0.5with concentrated hydrochloric acid, and the final solution wassonicated at 40° C. for 30 minutes.

[0194] A group of fasted, conscious rats were administered the dosingcompositions by oral gavage. Blood samples were collected by cardiacpuncture following the administration of ketamine (44 mg/kg). Heparinactivity was determined by utilizing the activated partialthromboplastim time (APTT) according to the method of Henry, J. B.,Clinical Diagnosis and Management by Laboratory Methods; Philadelphia,Pa.; W B Saunders (1979).

[0195] Results are illustrated in Table 6 below.

COMPARATIVE EXAMPLE 44A

[0196] Heparin (100 mg/kg) was' administered by oral gavage to rats, andheparin activity was determined according to the procedure of Example44.

[0197] Results are illustrated in Table 6 below. TABLE 6 In VivoDelivery of Heparin by Oral Administration Carrier Dose Drug Dose MeanPeak APTT Example Carrier (mg/kg) (mg/kg) (sec) 44 II 300 100 25.45 ±2.8   44A none none 100  20.7 ± 0.17 45 III 300 100 38.64 ± 17   46 V300 100  87.4 ± 34.1 47 XII 300 100 49.53 ± 17.1 48 XIX 300 100 119.99 ±56.3  49 XXXI  50  25 127.56 ± 22.97 50 XXXI  50  10 50.85 ± 9.1 

EXAMPLE 51

[0198] The method of Example 44 was followed, substituting low molecularweight heparin for the heparin and varying the amounts of propyleneglycol and water for solubilization as, necessary.

EXAMPLES 50-58 In Vivo Evaluation of Parathyroid Hormone in Rats

[0199] Preparation of Dosing Solutions.

[0200] The delivery agents were reconstituted with distilled waterand/or propylene glycol and adjusted to an apparent pH of 7.2-8.0 witheither aqueous hydrochloric, acid or aqueous sodium hydroxide. A stocksolution of parathyroid hormone was prepared by dissolving parathyroidhormone, in water. The parathyroid hormone solution was then added tothe delivery agent solution. Several different delivery agent to activeagent ratios were studied.

[0201] In Vivo Experiments

[0202] Male Sprague-Dawley rats weighing 200-250 g were fasted for 24hours and administered ketamine (44 mg/kg) and chlorpromazine (1.5mg/kg) 15 minutes prior to dosing. The rats were administered one of thedosing solutions described above by oral gavage or intracolonicinstillation. Blood samples were collected serially from the tail arteryfor serum determination of parathyroid hormone concentration. Serumparathyroid hormone concentrations were quantified by a parathyroidhormone radioimmunoassay test kit.

[0203] In Vivo Oral Administration.

[0204] Oral administration of solutions containing parathyroid hormone(PTH) and the non-α-amino acid delivery agents was tested in vivo inrats. The result show a significant increase in the oral bioavailabilityof parathyroid hormone as compared to similar administration of theactive agent alone. Data are presented in Table 7. TABLE 7 DeliveryAgent Enhancement of Parathyroid Hormone (PTH) Oral Bioavailability.Peak Carrier Active Serum Exam- Dose Method of Agent Dose [PTH] pleCarrier mg/kg Administration (μg/kg) (pg/mL) 51 CXXIII 100 intracolonic25 130 ± 20 52 CXXIII 250 oral 100  75 ± 25 53 CXXIII 250 oral 25  20 ±6 54 CVIII 100 intracolonic 25 115 ± 20 55 LXXXVI 100 intracolonic 25 40 ± 12 56 LVIII 100 intracolonic 25 145 ± 25 57 CXIV 100 intracolonic25  65 ± 15 58 LXXXIX 100 intracolonic 25  70 ± 15

[0205] The above mentioned patents, applications, test methods, andpublications are hereby incorporated by reference in their entirety.

[0206] Many variations of the present invention will suggest, themselvesto those skilled in the art in light of the above detailed description.All such obvious variations are within the full intended scope of theappended claims.

What is claimed is:
 1. A compound selected from the group consisting of

or salts thereof.
 2. A compound selected from the group consisting of

A Compound n m X XXXVII 0 0 4-Cl XXXVIII 3 0 H XXXIX 3 1 4-CH₃ XL 3 12-F XLI 3 1 2-CH₃ XLII 3 0 3-CF₃ XLIII 3 4 H XLIV 3 0 3-Cl XLV 3 0 3-FXLVI 3 0 3-CH₃ XLVII 0 0 2-CF₃ XLVIII 1 2 H XLIX 3 2 2-F L 3 03,4-OCH₂O— LI 3 0 2-COOH LII 1 0 2-OH LIII 3 0 2,6-dihydroxy LIV 2 02-OH LV 0 0 2,4-difluoro LVI 2 0 2,6-dihydroxy LVII 0 0 4-CF₃ LVIIl 3 03-NMe₂ LIX 2 0 3-NMe₂ LX 3 0 2,6-dimethyl LXI 3 .0 2-NO₂ LXII 3 0 2-CF₃LXIII 3 0 4-n-Pr LXIV 3 0 2-NH₂ LXV 3 0 2-OCH₃ LXVI 3 0 3-NO₂ LXVII 3 03-NH₂ LXVIII 2 0 2-NO₂ LXIX 2 0 2-NH₂ LXX 3 0 2-OCF₃ LXXI 2 0 2-OCH₃LXXII 2 0 2-OCF₃

or salts thereof.
 3. A compound selected from the group consisting of

B Compound n X LXXIII 3 4-CF₃ LXXIV 1 2-F LXXV 1 4-CF₃ LXXVI 33,4-dimethoxy LXXVII 0 3-OCH₃ LXXVIII 3 3-OCH₃ LXXIX 3 2,6-difluoro LXXX3 4-CH₃ LXXXI 1 4-OCH₃ LXXXII 2 2-F LXXXIII 0 2-F LXXXIV 2 4-OGH3 LXXXV0 2-OCH₃ LXXXVI 2 2-OCH₃ LXXXVII 0 4-CF₃ LXXXVIII 3 3-F LXXXIX 3 2-OCH₃

or salts thereof.
 4. A compound selected from the group consisting of

C Compound n m X XC 3 0 2-carboxycyclohexyl XCI 3 3 cyclohexyl XCII 3 02-adamantyl XCIII 3 0 1-morpholino

or salts thereof.
 5. A compound selected from the group consisting of

D Compound m XCIV 0 XCV 3

or salts thereof.
 6. A compound selected from the group consisting of E

Compound X XCVI OH XCVII ═O

or salts thereof.
 7. A compound selected from the group consisting of

F Compound n XCVIII 0 XCIX 2

or salts thereof.
 8. A compound selected from the group consisting of

G Compound n m X CXI 6 0 2-OH CXII 7 3 H CXIII 7 0 2-I CXIV 7 0 2-Br CXV7 0 3-NO₂ CXVI 7 0 3-N(CH₃)₂ CXVII 7 0 2-NO₂ CXVIII 7 0 4-NO₂ CXIX 9 02-OH

or salts thereof.
 9. A compound, selected from the group consisting of

H Compound X CXX 1-morphohno CXXI O-t-Butyl CXXII CH(CH₂Ph)NC(O)O-t-BuCXXIII 2-hydroxyphenyl

or salts thereof.
 10. A composition comprising (a) an active agent; and(b) a compound selected from the group consisting of

I

II

III

IV

V

VI

VII

VIII

IX

X

XI

XII

XIII

XIV

XV

XVI

XVII

XVIII

XIX

XX

XXI

XXII

XXIII

XXIV

XXV

XXVI

XXVII

XXVIII

XXIX

XXX

XXXI

XXXII

XXXIII

XXXIV

XXXV

XXXVI

CI

CII

CIII

CIV

CV

CVI

CVII

CVIII

CIX

CX

CXI

or salts thereof.
 11. A composition comprising (a) an active agent; and(b) a compound selected from the group consisting of A

Compound n m X XXXVII 0 0 4-Cl XXXVIII 3 0 H XXXIX 3 1 4-CH₃ XL 3 1 2-FXLI 3 1 2-CH₃ XLII 3 0 3-CF₃ XLIII 3 4 H XLIV 3 0 3-Cl XLV 3 0 3-F XLVI3 0 3-CH₃ XLVII 0 0 2-CF₃ XLVIII 1 2 H XLIX 3 2 2-F L 3 0 3,4-OCH₂O— LI3 0 2-COOH LII 1 0 2-OH LIII 3 0 2,6-dihydroxy LIV 2 0 2-OH LV 0 02,4-difluoro LVI 2 0 2,6-dihydroxy LVII 0 0 4-CF₃ LVIII 3 0 3-NMe₂ LIX 20 3-NMe₂ LX 3 0 2,6-dimethyl LXI 3 0 2-NO₂ LXII 3 0 2-CF₃ LXIII 3 04-n-Pr LXIV 3 0 2-NH₂ LXV 3 0 2-OCH₃ LXVI 3 0 3-NO₂ LXVII 3 0 3-NH₂LXVIII 2 0 2-NO₂ LXIX 2 0 2-NH₂ LXX 3 0 2-OCF₃ LXXI 2 0 2-OCH₃ LXXII 2 02-OCF₃

or salts thereof.
 12. A composition comprising (a) an active agent; and(b) a compound selected from the group consisting of B

Compound n X LXXIII 3 4-CF₃ LXXIV 1 2-F LXXV 1 4-CF₃ LXXVI 33,4-dimethoxy LXXVII 0 3-OCH₃ LXXVIII 3 3-OCH₃ LXXIX 3 2,6-difluoro LXXX3 4-CH₃ LXXXI 1 4-OCH₃ LXXXII 2 2-F LXXXIII 0 2-F LXXXIV 2 4-OCH₃ LXXXV0 2-OCH₃ LXXXVI 2 2-OCH₃ LXXXVII 0 4-CF₃ LXXXVIII 3 3-F LXXXIX 3 2-OCH₃

or salts thereof.
 13. A composition comprising (a) an active agent; and(b) a compound selected from the group consisting of C

Compound n m X XC 3 0 2-carboxycyclohexyl XCI 3 3 cyclohexyl XCII 3 02-adamantyl XCIII 3 0 1-morpholino

or salts thereof.
 14. A composition comprising (a) an active agent; and(b) a compound selected from the group consisting of D

Compound n XCIV 0 XCV 3

or salts thereof.
 15. A composition comprising (a) an active agent; and(b) a compound selected from the group consisting of E

Compound X XCVI OH XCVII ═O

or salts thereof.
 16. A composition comprising (a) an active agent; and(b) a compound selected from the group consisting of F

Compound n XCVIII 0 XCIX 2

or salts thereof.
 17. A composition comprising (a) an active agent; and(b) a compound selected from the group consisting of G

Compound n m X CXI 6 0 2-OH CXII 7 3 H CXIII 7 0 2-I CXIV 7 0 2-Br CXV 70 3-NO₂ CXVI 7 0 3-N(CH₃)₂ CXVII 7 0 2-NO₂ CXVIII 7 0 4-NO₂ CXIX 9 02-OH

or salts thereof.
 18. A composition comprising (a) an active agent; and(b) a compound selected from the group consisting of H

Compound X CXX 1-morpholino CXXI O-t-Butyl CXXII CH(CH₂Ph)NC(O)O-t-BuCXXIII 2-hydroxyphenyl

or salts thereof.
 19. A composition as defined in claim 10, wherein saidactive agent is selected from the group consisting of a biologicallyactive agent and a chemically active agent.
 20. A composition as definedin claim 19, wherein said biologically active agent is selected from thegroup consisting of a peptide, a mucopolysaccharide, a carbohydrate, alipid, a pesticide, or any combination, thereof.
 21. A composition asdefined in claim 20, wherein said biologically active agent is selectedfrom the group consisting of human growth hormone, bovine growthhormone, growth hormone-releasing hormone, an interferon, interleukin-IIinsulin, heparin, calcitonin, erythropoietin, atrial naturetic factor,an antigen, a monoclonal antibody, somatostatin, adrenocorticotropin,gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium,vancomycin, parathyroid hormone, desferrioxamine (DFO), or anycombination thereof.
 22. A composition as defined in claim 18,comprising parathyroid hormone and compound CXXIII or a salt thereof.23. A dosage unit form comprising (A) a composition as defined in claim10; and (B) (a) an excipient, (b) a diluent, (c) a disintegrant, (d) alubricant, (e) a plasticizer, (f) a colorant, (g) a dosing vehicle, or(h) any combination thereof.
 24. A dosage unit form according to claim23, comprising a tablet, a capsule, or a liquid.
 25. A method foradministering a biologically-active agent to an animal in need of saidagent, said method comprising administering orally to said animal acomposition as defined in claim
 10. 26 A method for preparing acomposition, said method comprising mixing: (A) at least onebiologically-active agent; (B) at least one compound as defined in claim1; and (C) optionally a dosing vehicle
 27. A method for administering anactive agent to an animal in need of said agent, said method comprisingadministering to said animal a composition as defined in claim 10wherein said composition is administered orally, intranasally,sublingually, intraduodenally, intramuscularly or subcutaneously.
 28. Amethod for preparing a compound having the formula

wherein Y is

or SO₂; R¹ is C₃-C₂₄ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkyne, cycloalkyl,or aromatic; R² is hydrogen, C₁-C₄ alkyl or C₂-C₄ alkenyl; and R³ isC₃-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl, thienyl, pyrrolo, or pyridyl,where R³ is optionally substituted by one or more C₁-C₅ alkyl group,C₂-C₄ alkenyl group, F, Cl, OH, SO₂, COOH or, SO₃H; said methodcomprising (a) reacting in water and the presence of a base, a compoundhaving the formula

with a compound having the formula R³—Y—X, wherein Y. R¹, R², and R³ areas above and X is a leaving group.
 29. A pharmacological compositioncomprising: (A) at least one biologically-active agent; and (B) at leastone carrier compound having the formula 2-HO—Ar—CONR⁸—R⁷—COOH  whereinAr is a substituted or unsubstituted phenyl or naphthyl; R⁷ is selectedfrom the group consisting of C₄ to C₂₀ alkyl, C₄ to C₂₀ alkenyl, phenyl,naphthyl, (C₁ to C₁₀ alkyl) phenyl, (C₁ to C₁₀ alkenyl) phenyl, (C₁ toC₁₀ alkyl) naphthyl, (C₁ to C₁₀ alkenyl) naphthyl, phenyl (C₁ to C₁₀alkyl), phenyl (C₁ to C₁₀ alkenyl), naphthyl (C₁ to C₁₀ alkyl), andnaphthyl (C₁ to C₁₀ alkenyl); R⁸ is selected from the group consistingof hydrogen, C₁ to C₄ alkyl, C₁ to C₄ alkenyl, C₁ to C₄ alkenyl,hydroxy, and C₁ to C₄ alkoxy; R⁸ is optionally substituted with C₁ to C₄alkyl, C₁ to C₄ alkenyl, C₁ to C₄ alkoxy, —OH, —SH and —CO₂R⁹ or anycombination thereof; R⁹ is hydrogen, C₁ to C₄ alkyl or C₁ to C₄ alkenyl;R⁷ is optionally interrupted by oxygen, nitrogen, sulfur or anycombination thereof; with the proviso that the compounds are notsubstituted with an amino group in the position alpha to the acid group;or salts thereof.